• An experimental drug from Intercept Pharmaceuticals helped improve liver scarring in patients with non-alcoholic steatohepatitis, or NASH, in a large Phase 3 study, making for the first late-stage success to result from surging drugmaker testing of treatments for the fatty liver disease.
• Positive data in hand, Intercept plans to submit its drug, called obeticholic acid, to regulators in the U.S. and Europe later this year, potentially positioning the biotech as first to market with a treatment for a disease forecast to soon become the leading cause of liver transplants in the U.S.
• While Intercept’s data mark a major milestone for the NASH field, the result comes with several caveats that temper the company’s success. Treatment with obeticholic acid did not resolve NASH in significantly more patients than did placebo, and the drug’s safety profile could pose challenges if approved. 

Intercept has played the role of catalyst before.

Five years ago, positive results from a smaller study of obeticholic acid in NASH served as a starting gun for a field that’s grown to include major pharmaceutical firms as well as dozens of biotechs. 

Then, Intercept’s success led to a six-fold increase in the company’s stock price, which soared from just over $70 per share to reach above $460 a piece in the period of just two months. Now, following the first Phase 3 NASH success, Intercept’s 15% stock jump to near $130 per share Tuesday reflects a field more measured in its expectations for potential treatments. 

Several major drugmakers in the space have concluded NASH’s complex nature will require combination treatment, while heady Wall Street forecasts of pharma’s next big market now incorporate a greater understanding of the commercial challenges presented by a disease considered to be a “silent epidemic.”

Clinical success is no sure thing, either. Earlier this month, Gilead Sciences reported its lead candidate for NASH failed, showing essentially no difference versus placebo in improving fibrosis. 

Estimates put the prevalence of NASH, which stems from the steady build-up of fat in the liver, anywhere from as low as 3% of the U.S. adult population to as high as 12%. NASH triggers inflammation, resulting in liver scarring and, eventually, cirrhosis.

Phase 3 success

Intercept now looks positioned to potentially win the first approval for a NASH treatment. Yet results from its study, dubbed REGENERATE, also leave room for potential competitors to improve on obeticholic acid’s performance in the future.

Data unveiled Tuesday by Intercept showed obeticholic acid led to an improvement of one stage or greater in fibrosis without worsening of NASH at 18 months in 23% of patients given a high dose of the drug. That was statistically superior to the roughly 12% of patients on placebo who also saw a fibrosis improvement.

Only patients with stage 2 or stage 3 liver fibrosis were included in that analysis. Intercept also enrolled an exploratory cohort of 287 NASH patients with stage 1 liver fibrosis. Across the broader group, 21% of patients on high dose obeticholic acid experienced an improvement in fibrosis versus less than 11% on placebo. 

No other drug has shown an anti-fibrotic effect in a late-stage study of NASH patients. In its study, Intercept confirmed NASH with fibrosis using biopsies at baseline, and then conducted a repeat biopsy at 18 months to assess the drug’s effect. 

Obeticholic acid did not, however, lead to significantly more frequent resolution of NASH without worsening of fibrosis — the study’s other primary endpoint. About 12% of patients given the high dose of Intercept’s drug met that measure, compared to 8% on placebo.

The Food and Drug Administration accepts both endpoints — improvement in fibrosis and NASH resolution — as supportive of a potential approval. Intercept also tested a lower dose of obeticholic acid that did not perform as well compared to placebo.

Safety questions

Importantly, obeticholic acid comes with a side effect profile that could present hurdles to patient uptake if the drug were to win approval. 

Half of patients on the high dose of the drug experienced dose-related pruritis, or itching. Most pruritus events were mild to moderate, but severe pruritis occurred in 5% of those enrolled in the high-dose arm. According to the trial plan, any incidence of severe pruritus required treatment discontinuation, and pruritus-related halting of treatment was reported in 9% of patients given the higher dose.

Pruritus is a notable side effect, because many NASH patients don’t see symptoms until later stages of the disease. 

Intercept plans to discuss dose titration with the FDA as a potential approach to mitigate the effect of pruritus. 

Three percent of patients on high dose obeticholic acid experienced hepatobiliary events, a potential concern given the drug’s black box warning for its approved condition, primary biliary cholangitis. 

Intercept’s not the only biotech with a Phase 3 dataset in 2019. Results are expected from French biotech Genfit in the back half of this year, while Gilead still has data to report from a second late-stage study testing its now once-failed drug selonsertib.

Full results from REGENERATE will be presented at the International Liver Congress in April, Intercept said.